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Development of Non-Targeted Approaches to Evidence Emerging Chemical Hazard

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Development of Non-Targeted Approaches to Evidence Emerging Chemical Hazard THESE DE DOCTORAT DE ONIRIS COMUE UNIVERSITE BRETAGNE LOIRE ECOLE DOCTORALE N° 605 Biologie Santé Spécialité : Santé Publique Par Mariane POURCHET Development of non-targeted approaches to evidence emerging chemical hazard Identification of new biomarkers of internal human exposure, in order to support human biomonitoring and the study of the link between chemical exposure and human health Thèse présentée et soutenue à Nantes, le 8 octobre 2020 Unité de recherche : LABERCA UMR INRAE 1329 Rapporteurs avant soutenance : Benedikt WARTH Associate professor, University of Vienna, Vienna, Austria Katrin VORKAMP Doctor, Aarhus University, Aarhus, Denmark Development of non-targeted approaches to evidence emerging Composition du Jury : chemical hazard Président : Adrian COVACI Professor, University of Antwerp, Antwerp, Belgium ExaminateursIdentification : Benedikt of WARTHnew biomarkers Associateof internal professor, human University exposure, of Vienna, in Vienna, order Austria to support Katrin VORKAMP Doctor, Aarhus University, Aarhus, Denmark human biomonitoringJana KLANOVA and the studyProfessor, of the Masaryk link University,between Brno, chemical Czech Republic exposure and Adrian COVACI Professor, University of Antwerp, Antwerp, Belgium human health Dir. de thèse : Jean-Philippe ANTIGNAC Doctor, Oniris, Nantes, France Thèse présentée et soutenue à Nantes, le 8 octobre 2020 Unité de recherche : LABERCA UMR INRAE 1329 I would like to express my sincere gratitude to my thesis committee, Benedikt Warth, Associate professor, Department of Food Chemistry and Toxicology, University of Vienna, Austria Katrin Vorkamp, Senior researcher, Department of Environmental Science, Aarhus University, Denmark Adrian Covaci, Professor, Toxicological Centre, University of Antwerp, Belgium Jana Klánová Professor, Research Centre for Toxic Compounds in the Environment (RECETOX), Masaryk University, Brno, Czech Republic for their time in reading and evaluating this manuscript. Les présents travaux de thèse réalisés au LABERCA m’ont amenée à faire de nombreuses rencontres. Je tiens à exprimer ma sincère gratitude et à remercier l’ensemble des acteurs qui m’ont accompagnée pendant ces trois années. Je tiens à remercier sincèrement Bruno Le Bizec, directeur du LABERCA, pour m’avoir accueillie dans un environnement scientifiquement et humainement propice au travail, ainsi que pour votre regard critique et bienveillant sur mon travail. Un grand merci à Jean-Philippe Antignac, directeur de thèse, pour m’avoir accompagnée pendant ces trois années. Merci également pour l’autonomie que tu m’as accordée et pour nos nombreuses discussions qui m’ont permises d’enrichir mes connaissances aussi bien en sciences qu’en gestion de projet. Aux membres de mon comité de suivi individuel, Laurent Debrauwer et Jean-Charles Martin, je vous remercie pour le temps que vous avez consacré à évaluer en toute bienveillance mes travaux ainsi que pour vos précieux conseils. I want to express my gratitude to all HBM4EU partners for all the interesting discussions we had during meetings and conferences. I also want to thank Marja Lamoree, Jeroen Meijer and the team members of the VU-E&H, as well as Jana Klanova, Elliott Price and the team members of RECETOX for the wonderful secondments I had in Amsterdam and Brno and for sharing their knowledge. I want to thank the University of Granada and the University of Masaryk for sending placenta and meconium samples. Merci à Ronan Cariou, pour m’avoir accompagnée dans le laboratoire, ton enthousiasme et ta rigueur. Je souhaite un grand succès à HaloSeeker ! Merci à Emmanuelle Bichon, pour m’avoir guidée sur le développement de mes méthodes et pour m’avoir écoutée. Je souhaite une longue vie au CCOA ! Merci à Ingrid Guiffard, ma maman de labo, pour m’avoir formée à l’utilisation de la GPC, guidée sur le choix des standards et surtout pour ton soutien sans faille. Merci à Gaud Dervilly, pour m’avoir accompagnée depuis notre discussion à la fin d’un cours de master jusqu’à l’obtention d’un poste post-thèse Merci à Yann Guitton et Sébastien Hutinet, pour le développement des outils informatiques, votre disponibilité et l’effort conjoint pour que l’on parle la même langue. Merci aux membres de la plateforme, Fabrice Monteau, Karinne Pouponneau, Marie- Line Morvan, Stéphanie Prévost et Sadia Ouzia, pour m’avoir formée sur les instruments, aidée à trouver mes repères dans le laboratoire et initiée à Galaxy. Merci à Anne-Lise Royer, pour tes conseils en métabolomique, ta bonne humeur ainsi que tous les bons moments passés ensemble. Merci à l’ensemble de l’équipe UCO, pour le partage de connaissances, l’enregistrement de standards et surtout pour votre aide sur les expériences ciblées. Merci aux membres UPC et ATI pour le partage du matériel, de votre temps et de vos connaissances. Merci à Florence Ramdin, Lucie Besecque et Virginie Klingler pour votre aide dans les différentes tâches administratives, avec parfois quelques nœuds au cerveau pour gérer les budgets extérieurs. Merci pour votre patience et votre réactivité. Cette thèse n’aurait pas été la même sans l’équipe de Docs & Co, à l’intérieur comme à l’extérieur du bocal. Je tiens à remercier l’ensemble des doctorants et post-doctorants passés ou encore présents, pour la perpétuelle bonne humeur et pour l’esprit familial que vous avez créé. Malgré un épisode Covid non propice aux interactions sociales, je garde de très bons souvenirs du club fromage, du Monday cake et des repas de Noël, des mots-fléchés, des photos de groupes et du calendrier de l’Avent. Merci à Marie, ma sœur de thèse et confidente, pour nos discussions entre nos deux bureaux, ton soutien et tous les bons moments passés ensemble ; à mes mamans de bureau Léa et Elsa, toujours de bonne humeur et prêtes à partager les derniers potins ; Maykel, mon grand frère de labo, pour ta grande gentillesse, ton soutien et les cours d’espagnol ; Caroline, pour ta positive-attitude en toute circonstance et ton soutien (merci également pour la relecture du manuscrit et la valorisation de mon travail) ; Jérémy, pour tes blagues, imitations et références filmographiques toujours bien dosées (merci aussi pour la correction de l’anglais du manuscrit, j’ai beaucoup ri en lisant certains commentaires). Merci à Manon, pour m’avoir motivée à aller aux séances de sport quand il pleuvait ; Luca, pour avoir pris le temps de m’apprendre les bases des modèles OPLS et pour les succulentes spécialités italiennes que tu nous as fait (re)découvrir (mozza, noisettes, fromages, charcuterie) ; Julien, ou devrais-je dire Satan, mais avec un cœur en guimauve ; Gabriel, le cycliste engagé, avec un jeu de mots pour chaque situation ; Komodo, pour ton ouverture d’esprit ; Ahmed, l’incarnation de la sagesse et de la gentillesse ; Alexis, pour m’avoir guidée sur mes premières manips et pour ton grand cœur ; Inas, dont la générosité dépasse les limites du réel ; Chloé, pour ton dynamisme et ta diarrhée orale ; Mikaïl, le grand gaillard musclé qui ne ferait pas de mal à une petite mouche. Thomas et Yoann, les inséparables ou presque, toujours le sourire aux lèvres et prêts à blaguer. Merci également à Annabelle et Lucie, pour avoir tenté l’expérience d’un stage sous ma tutelle, je vous souhaite de vous épanouir dans votre carrière. A tous mes amis en dehors du laboratoire, je vous remercie pour les merveilleux moments que je passe en votre compagnie et pour la curiosité que vous avez apportée à ma thèse, surtout autour de ce fameux « cacanium ». Un énorme merci à ma famille, ma petite sœur Malaurie, mon oncle Manou et principalement à ma maman qui a toujours eu confiance en moi et sans qui je ne serai pas la personne que je suis aujourd’hui. Merci à mon compagnon Raphaël, pour me cuisiner des bons petits plats chaque jour et pour l’amour dont tu me gâtes à chaque instant. TABLE OF CONTENTS Table of contents TABLE OF CONTENTS ...................................................................................................................................... 11 RESUME DE LA THESE EN FRANCAIS ............................................................................................................... 17 GENERAL INTRODUCTION .............................................................................................................................. 27 CHAPTER 1 ..................................................................................................................................................... 33 NON-TARGETED SCREENING OF BIOMARKERS OF HUMAN INTERNAL CHEMICAL EXPOSURE: STATE-OF-THE- ART AND CHALLENGES ................................................................................................................................... 33 1.1. HUMAN CHEMICAL EXPOSURE: CONTEXT AND CHALLENGES ..................................................................................... 35 1.1.1. The Exposome concept ...................................................................................................................... 35 1.1.2. Chemical contaminants ..................................................................................................................... 35 1.1.3. Routes of external human exposure to chemical contaminants ........................................................ 37 1.1.4. Internal exposure and Absorption, Distribution, Metabolism and Excretion (ADME) processes ....... 38 1.1.5. Focus on early life stage of exposure ................................................................................................. 41 1.2. HUMAN
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